Advanced paternal age is less well publicized than advanced maternal age, but paternal age can also have a significant impact on reproductive health. Approximately 5% of liveborn human offspring have a genetic disorder and of these, approximately 20% are due to germline de novo mutations. Several autosomal dominant disorders are associated with advanced paternal age. These data indirectly indicate an increased mutant frequency in the male germline with age. The mechanisms mediating the increased mutant frequency are not understood. Our long-term goal is to identify and delineate the mechanisms by which DMAintegrity is lost with advanced paternal age. Toward this end, we identified a mouse model, the lacl transgenic mouse line, that exhibits increased spontaneous mutant frequencies in the lacl transgene recovered from spermatogenic cells of older mice. We propose to use the lacl transgenic mouse model in our efforts to define the molecular mechanisms involved in advanced paternal age. The hypothesis to be tested is that the ability to maintain male germline DMAintegrity declines with increased age. The specific aims are: 1) to assess base excision repair activity in nuclear extracts prepared from spermatogenic cells obtained from mice at various ages, 2) to assess the role of apoptosis in male germline DMAintegrity at various ages, and 3) to determine the impact of induced DMAdamage in male germ cells of mice at various ages. The studies are focused on understanding the contribution of pathways that are believed to contribute substantially to maintaining genetic integrity, namely the DNA base excision repair pathway and apoptosis. This study will advance our understanding of the fundamental mechanisms involved in male germline integrity.